Cytoadherence and sequestration in malaria transmission stages

描述（由申请人提供）：细胞粘附和感染红细胞的隔离是恶性疟原虫疟疾的标志。以前的研究强调了结复合物的主要贡献，特别是主要的寄生虫抗原，PfEMP 1，在介导细胞粘附在最后20小时的无性发育的恶性疟原虫寄生虫。恶性疟原虫的成熟性阶段仅在发育8-10天后出现在外周血中，解剖学小生境中的不成熟性阶段的隔离对于这些寄生虫成功传播给蚊子媒介绝对至关重要。解剖学上的小生境在哪里？有性阶段细胞粘附的分子基础是什么？本申请中概述的实验方法旨在区分发育中的有性阶段诱导细胞粘附的三种可能的机制，并鉴定患者组织中相应的隔离概况：i）发育中的有性阶段通过与无性阶段相同的决定因子细胞粘附，即，相同的PfEMP 1在感染的红细胞表面上表达。这将导致无性和有性阶段的螯合概况在很大程度上重叠。ii）它们通过相同的机制在无性阶段进行细胞粘附，但使用不同的决定子，即，a PfEMP 1特异于性发育。这种情况可能会导致配子体特异性隔离位点，类似于表达保守PfEMP 1变体的寄生虫的胎盘隔离。iii）它们通过完全不同的机制细胞粘附，即，PfEMP 1以外的分子（或一类分子）。在这种情况下，螯合概况也将不同于无性阶段。性恶性疟原虫阶段是基于药物和疫苗的策略的主要目标，以阻止寄生虫在流行地区的传播。在目前使用的几乎完全针对红细胞内无性发育的药物制剂普遍存在抗药性的情况下，传播阻断战略重新引起了人们的兴趣，现在已成为全世界减少疟疾负担努力的一个主要重点。拟议的实验与这些努力是一致的，因为它们旨在阐明人类宿主中疟疾传播阶段的生存和发展的关键机制。

DESCRIPTION (provided by applicant): Cytoadherence and the resulting sequestration of infected red blood cells are a hallmark of P. falciparum malaria. Previous studies have emphasized the major contribution of the knob complex and particularly the major parasite antigen, PfEMP1, in mediating cytoadherence during the last 20 hours of asexual development of P. falciparum parasites. Mature sexual stages of P. falciparum only appear in the peripheral blood after 8-10 days of development, and sequestration of immature sexual stages in anatomical niches must be absolutely crucial for successful transmission of these parasites to the mosquito vector. Where is that anatomical niche, and what is the molecular basis for cytoadherence in sexual stages? The experimental approaches outlined in this application aim to distinguish the three possible mechanisms by which developing sexual stages induce cytoadherence, and to identify the corresponding sequestration profiles in patient tissues: i) Developing sexual stages cytoadhere through the same determinants as asexual stages, i.e., the same PfEMP1 is expressed on the infected red blood cell surface. This would result in largely overlapping sequestration profiles for asexual and sexual stages. ii) They cytoadhere through the same mechanisms asexual stages, but using a different determinant, i.e., a PfEMP1 specific to sexual development. This situation would likely result in gametocyte-specific site of sequestration, similar to placental sequestration of parasites expressing a conserved PfEMP1 variant. iii) They cytoadhere through a different mechanism altogether, i.e., a molecule (or class of molecules) other than PfEMP1. In this case, the sequestration profile would also be different from that of asexual stages. Sexual P. falciparum stages are a major target for both drug- and vaccine-based strategies to block transmission of the parasite in endemic areas. In the context of widespread resistance against the currently used drug formulations that almost exclusively target asexual development within the red blood cell, transmission-blocking strategies have gained renewed interest and are now a major focus of worldwide efforts to reduce the burden of malaria. The proposed experiments are in line with these efforts as they aim to elucidate a mechanism crucial for the survival and development of malaria transmission stages in the human host.